A 36-year-old man is evaluated due to swelling and severe pain of the right foot. Medical history is significant for kidney transplant due to focal segmental glomerulosclerosis. The patient is diagnosed with gout and treated with prednisone. Six weeks later, the patient is seen at follow-up. He has no foot pain and the swelling has subsided. Serum uric acid level is 13.5 mg/dL and creatinine level is 0.9 mg/dL. Allopurinol is prescribed. Initiation of this drug would most likely increase the activity of which of the following medications?

Question

A 36-year-old man is evaluated due to swelling and severe pain of the right foot.  Medical history is significant for kidney transplant due to focal segmental glomerulosclerosis.  The patient is diagnosed with gout and treated with prednisone.  Six weeks later, the patient is seen at follow-up.  He has no foot pain and the swelling has subsided.  Serum uric acid level is 13.5 mg/dL and creatinine level is 0.9 mg/dL.  Allopurinol is prescribed.  Initiation of this drug would most likely increase the activity of which of the following medications?

Quizplus · Accepted Answer

11ec160b_3c78_9711_9249_f58bc451da49_MD0001_00 In the purine degradation pathway, purine bases (ie, hypoxanthine, guanine) can follow 1 of 2 routes: Approximately 10% are converted by xanthine oxidase to uric acid, which is released into the bloodstream and excreted in the urine. The other 90% are recycled into purine nucleotides by hypoxanthine-guanine phosphoribosyltransferase (HGPRT) to be reused in the formation of DNA and RNA (ie, purine salvage). Gout occurs due to elevated serum uric acid levels, leading to the formation of inflammation-inducing uric acid crystals within joints (eg, metatarsals). Xanthine oxidase inhibitors (eg, allopurinol, febuxostat) treat gout by reducing uric acid levels and in the process shunt additional purine bases toward the salvage route. Azathioprine is an immunosuppression drug that is metabolized via the purine degradation pathway. Following ingestion, azathioprine is converted to 6-mercaptopurine (6-MP), which is a false purine base that, like hypoxanthine and guanine, can follow 1 of 2 routes. Some 6-MP is converted by xanthine oxidase (or thiopurine methyltransferase) into inactive metabolites that are excreted in the urine. The remainder is converted by HGPRT into active metabolites (6-thioguanines), which act as false nucleotides that incorporate into DNA and RNA and inhibit hematopoietic cell proliferation. Therefore, when a xanthine oxidase inhibitor is combined with azathioprine, 6-MP is shunted toward conversion into active metabolites, leading to increased immunosuppression and risk of cellular toxicity. (Choice B) Ganciclovir is similar in structure to guanosine and forms false purine nucleotides that disrupt DNA synthesis. It is relatively specific for viral DNA replication enzymes; it does not interact with allopurinol because it is not catabolized by xanthine oxidase. (Choices C and D) Prednisone exerts a nonspecific immunosuppressive effect by inhibiting NF-kB to regulate the transcription of leukoproliferative cytokines. Tacrolimus is a calcineurin inhibitor that suppresses T cells by preventing IL-2 transcription. Neither drug targets the purine degradation pathway and therefore is not significantly influenced by xanthine oxidase inhibition. (Choice E) Trimethoprim inhibits dihydrofolate reductase to disrupt folate metabolism and inhibit the production of pyrimidine nucleotides. It is not affected by the inhibition of xanthine oxidase in the purine degradation pathway. Educational objective: Azathioprine is an immunosuppression drug that is metabolized into active metabolites by HGPRT and, conversely, inactivated by xanthine oxidase. Coadministration with a xanthine oxidase inhibitor (eg, allopurinol, febuxostat) shunts azathioprine metabolism toward the production of active metabolites, resulting in increased immunosuppression and risk of cellular toxicity. __________ References: Myelosuppression associated with azathioprine-allopurinol interaction after heart and lung transplantation. (http://www.ncbi.nlm.nih.gov/pubmed/8669118)

A 36-Year-Old Man Is Evaluated Due to Swelling and Severe